For many years, drugs that alter sympathoadrenal function at ocular postjunctional beta adrenoceptors have been used in the chronic therapy of open-angle glaucoma. More recently alpha2 and DA2 receptor agonists have been demonstrated to lower intraocular pressure in glaucomatous humans, but their modes of action have not been clearly defined. Results from this laboratory suggest that alpha2 adrenoceptors, modulating aqueous humor dynamics, are heterogenous and located at multiple sites including the brain stem, postganglionic sympathetic nerves and nonpigmented ciliary epithelium, whereas DA2 receptors are located predominantly on postganglionic sympathetic nerves. Preliminary evidence indicates that certain alpha2 agonists, with imidazoline-like structures, act on receptors (imidazoline, I1) that can be distinguished from classical alpha2-adrenoceptors. The overall objective of this research project is to delineate the sites and mechanisms of action of alpha2, I1 and DA2 agonists at the organ, tissue and cellular levels. Using sequential administration of relatively selective agonists and antagonists onto the eye and into selected areas of the brainstem, in vivo studies will define the relative roles of ocular and central alpha2/I1 receptors in regulating aqueous humor dynamics. Analysis of agonist and antagonist action on isolated rabbit and human iris-ciliary bodies (ICB) will provide in vitro evidence for modification of release of norepinephrine from sympathetic neurons and signal transduction pathways in the ciliary epithelium. Functional evidence will be sought for the possibility that alpha2 receptors in ICBs from African-Americans are less sensitive to agonists than those of Caucasians. At the cellular level, actions of alpha2, I1 and DA2 agonists will be delineated on cyclic nucleotides, G proteins and ion channels in freshly isolated and cultured sympathetic neurons and nonpigmented epithelial cells utilizing image analysis, patch clamp methods and other techniques. Results from this project will provide a rationale for: 1) using alpha2, I1 and DA2 agonists in the therapy of glaucoma and 2) developing novel antiglaucoma agents that directly influence specific components of signal transduction pathways.